NM_005378.5:c.1340T>C (p.Leu447Ser) is a missense variant in MYCN, located within the C-terminal leucine zipper domain critical for protein dimerization and DNA binding. The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.1 PM1 (moderate) is met: residue Leu447 lies within the MYCN leucine zipper domain, a well-established critical functional domain. The variant is absent from population databases, consistent with a lack of benign variation in this region.2 PM2 (supporting) is met: the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency <0.1%).3 PVS1 is not applicable: the variant is a missense substitution and does not qualify as a predicted null variant under PMC6185798.4 PP3 is not met: in silico predictors are conflicting (REVEL 0.767 damaging, BayesDel 0.164 neutral). BP4 is also not met for the same reason.5 BP1 is not met: missense variants in MYCN are a known disease mechanism for Feingold syndrome type 1 and megalencephaly-polydactyly syndrome. With one moderate criterion (PM1) and one supporting criterion (PM2), this combination does not reach the Likely Pathogenic threshold under generic ACMG/AMP 2015 combination rules (PMID:25741868). The variant is classified as a Variant of Uncertain Significance (VUS).6
MYCN
Final classification
VUS
PM1PM2
MYCN
c.1340T>C
p.Leu447Ser
This variant
NM_005378.5:c.1340T>C (p.Leu447Ser) is a missense variant in MYCN, located within the C-terminal leucine zipper domain critical for protein dimerization and DNA binding. The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 moderate, PM2 supporting; combination = 1 moderate + 1 supporting, which maps to VUS.
Classification rationale
PM1PM2
VUS
MYCN c.1340T>C
PM1 + PM2
→
VUS
4
pvs1_generic_framework ↗pvs1_variant_assessment
5
revelbayesdelspliceai ↗
6
generic_acmg_combination_rules
Gene diagram
· NM_005378.5 · variants mapped to exon structure
MYCN
NM_005378.5
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 21 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM1
moderate
review
Pathogenic
Residue Leu447 is located within the C-terminal leucine zipper domain of MYCN (approximately residues 440-464), a well-established critical functional domain required for protein dimerization and DNA binding. The variant is absent from gnomAD, consistent with a lack of benign variation in this domain.
Leu447 resides in the leucine zipper domaincritical for MYCN dimerization and DNA binding. Variant absent from all gnomAD populations.
✓
PM2
supporting
Pathogenic
NM_005378.5:c.1340T>C is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, meeting the PM2 threshold of <0.1% population allele frequency under generic ACMG/AMP rules.
Absent from gnomAD v2.1 (exomes)gnomAD v4.1 (exomes)and gnomAD-Canada v1.0 (genomes). Allele count = 0 across all population databases.
Assessed · not applied
· 5 not met · 16 not assessed
Pathogenic
PS1
No known pathogenic variant at the same amino acid residue (Leu447) with a different nucleotide change has been identified.
PS2
No de novo occurrence data with confirmed paternity and maternity are available for this variant.
PS3
No well-established functional studies demonstrating a damaging effect have been identified for NM_005378.5:c.1340T>C (p.Leu447Ser).
PS4
No case-control or cohort studies reporting this variant in affected individuals have been identified.
PM5
No pathogenic missense variant at the same amino acid residue (Leu447) with a different amino acid change has been identified.
PM6
No de novo observation (without confirmation of paternity and maternity) has been identified for this variant.
PP1
No co-segregation data are available for NM_005378.5:c.1340T>C.
PP2
Gene-level constraint data are not available for MYCN (HCI prior not found), and gnomAD missense constraint metrics (Z-score, o/e) were not retrieved.
PP3
In silico predictions are conflicting: REVEL score of 0.767 falls in the damaging range (≥0.5), but the BayesDel score of 0.164 is in the neutral/benign range.
PP4
No patient phenotype or family history data are available for this variant.
PP5
This variant has not been reported as pathogenic by a reputable source.
Benign
BA1
NM_005378.5:c.1340T>C is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS1
NM_005378.5:c.1340T>C is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS2
No data are available regarding observation of this variant in healthy adults with full penetrance expected at an early age.
BS3
No well-established functional studies demonstrating no damaging effect have been identified for this variant.
BS4
No segregation data are available to assess lack of co-segregation with disease.
BP1
Missense variants in MYCN are a known disease mechanism.
BP2
No evidence of observation in trans with a pathogenic variant is available.
BP4
The REVEL score of 0.767 falls in the damaging range, and SpliceAI shows no splice impact (max delta 0.01).
BP5
No evidence is available that this variant has been observed in a case with an alternate molecular basis for disease.
BP6
This variant has not been reported as benign by a reputable source.
N/A · 5
PVS1 · PM3 · PM4 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.767. BayesDel score = 0.163771.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MYCN, a transcription factor, is altered by amplification and overexpression in a variety of cancer types including in neuroblastoma.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links